Page 50 - N. Metabolism and metabolic diseases

[N. Metabolism and metabolic diseases-32]

WDR76 mediates obesity and hepatic steatosis via HRas

destabilization

Seol Hwa Seo¹˙², Jong-Chan Park¹˙², Woo-Jeong Jeong¹˙², Kang-Yell Choi¹˙²˙³

¹Translational Research Center for Protein Function Control, Yonsei University, Seoul 03722, Korea, ²Department of

Biotechnology, Yonsei University, Seoul 03722, Korea, ³CK Biotechnology Inc., CK Biotechnology Inc., Seoul 03722,
Korea

Ras/MAPK (mitogen active protein kinase) signaling plays contradictory roles in adipocyte differentiation and is

tightly regulated during adipogenesis. However, mechanisms regulating adipocyte differentiation involving Ras

protein stability regulation are unknown. Here, we show that WD40 repeat protein 76 (WDR76), a novel Ras
regulating E3 linker protein, controls 3T3-L1 adipocyte differentiation through HRas stability regulation. The roles
of WDR76 in obesity and metabolic

regulation were characterized using a high-fat diet (HFD)-induced obesity model using Wdr76−/− mice and liver-
specific Wdr76 transgenic mice (Wdr76Li−TG). Wdr76−/− mice are resistant to HFD-induced obesity, insulin

resistance and hyperlipidemia with an increment of HRas levels. In contrast, Wdr76Li-TG mice showed increased
HFD-induced obesity, insulin resistance with reduced HRas levels. Our findings suggest that WDR76 controls HFD-

induced obesity and hepatic steatosis via HRas destabilization. These data provide insights into the links between
WDR76, HRas, and obesity.